Differences in Formation of Prepuce and Urethral Groove During Penile Devel-Opment Between Guinea Pigs and Mice Are Controlled by Differential Expression of Shh, Fgf10 and Fgfr2

The penile tubular urethra forms by canalization of the urethral plate without forming an obvious urethral groove in mice, while urethral epithelium forms fully opened urethral groove before urethra closure through dis-tal-opening-proximal-closing process in humans and guinea pigs. Our knowledge about the mechanism of penile development is mainly based on the studies in mice. To reveal how the fully opened urethral groove forms in humans and guinea pigs, we compared the expression patterns and levels of key developmental genes using in situ hybridization and quantitative PCR during glans and preputial de-velopment between guinea pigs and mice. Our results revealed that compared with preputial development which started before sexual differentiation in mice, the preputial development in guinea pigs was delayed and initiated at the same time as sexual differentiation began. Fgf10 was mainly expressed in urethral epi-thelium in developing genital tubercle (GT) of guinea pigs, relative expression of Shh, Fgf8, Fgf10, Fgfr2 and Hoxd13 reduced more than 4-fold in GT of guinea pigs compared with in that of mice. Hedgehog and Fgf inhibitors induced ure-thral groove formation and restrained preputial development in cultured mouse GT, while Shh and Fgf10 proteins induced preputial development in cultured guinea pig GT. Our discovery suggests that differential expression of Shh and Fgf10/Fgfr2 may be the main reason that a fully opened urethral groove forms in guinea pigs, and maybe it’s the same with humans as well.